High rates of relapse to drug use after long periods of abstinence characterize the behavior of experienced users of alcohol. An important factor for provoking relapse to alcohol in humans is exposure to stress. However, until recently a preclinical model to study this phenomenon under controlled experimental conditions did not exist. We have developed a reinstatement procedure to study the effect of exposure to stress on relapse to alcohol seeking in alcohol-experienced rats that are drug-free at the time of testing. In the reinstatement procedure, the ability of acute exposure to drug or non-drug stimuli to reinstate drug seeking is examined after training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We have shown that brief exposure to intermittent footshock stress potently reinstates alcohol seeking in alcohol-experienced rats that are drug-free at the time of tests for relapse. These data provide the first preclinical demonstration of stress-induced relapse to alcohol seeking. Subsequently, we have found that the serotonin reuptake blocker, fluoxetine, and corticotropin-releasing factor (CRF) receptor antagonists attenuate stress-induced relapse to alcohol. On the basis of these findings, we now propose to further characterize neurochemical and environmental events involved in relapse to alcohol induced by stressors. Characterization of the relapse process in our preclinical model may lead to the development of medications for relapse prevention in humans.